ZA200503698B - Process for making risperidone and intermediates therefor - Google Patents
Process for making risperidone and intermediates therefor Download PDFInfo
- Publication number
- ZA200503698B ZA200503698B ZA200503698A ZA200503698A ZA200503698B ZA 200503698 B ZA200503698 B ZA 200503698B ZA 200503698 A ZA200503698 A ZA 200503698A ZA 200503698 A ZA200503698 A ZA 200503698A ZA 200503698 B ZA200503698 B ZA 200503698B
- Authority
- ZA
- South Africa
- Prior art keywords
- isomer
- oxime
- formula
- process according
- acetic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 64
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 title claims description 46
- 229960001534 risperidone Drugs 0.000 title claims description 46
- 230000008569 process Effects 0.000 title claims description 40
- 239000000543 intermediate Substances 0.000 title description 4
- 150000002923 oximes Chemical class 0.000 claims description 144
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 60
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001556 precipitation Methods 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- 159000000021 acetate salts Chemical class 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 230000002152 alkylating effect Effects 0.000 claims description 6
- 230000001376 precipitating effect Effects 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical group N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- -1 benzisoxazole compound Chemical class 0.000 description 25
- 239000002585 base Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 5
- 230000002269 spontaneous effect Effects 0.000 description 5
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical group C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- QPJONRGTWKXJLG-UHFFFAOYSA-N (2,4-difluorophenyl)-piperidin-4-ylmethanone;hydrochloride Chemical compound Cl.FC1=CC(F)=CC=C1C(=O)C1CCNCC1 QPJONRGTWKXJLG-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- OPYLAGAQMHMBNY-UHFFFAOYSA-N 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one;hydrochloride Chemical compound Cl.C1CCCN2C(=O)C(CCCl)=C(C)N=C21 OPYLAGAQMHMBNY-UHFFFAOYSA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000006333 difluoro benzoyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42572702P | 2002-11-13 | 2002-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200503698B true ZA200503698B (en) | 2006-08-30 |
Family
ID=32313043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200503698A ZA200503698B (en) | 2002-11-13 | 2005-05-09 | Process for making risperidone and intermediates therefor |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US7405298B2 (fr) |
| EP (1) | EP1560814A1 (fr) |
| CN (1) | CN100390146C (fr) |
| AR (1) | AR041954A1 (fr) |
| AU (1) | AU2003288017A1 (fr) |
| HR (1) | HRP20050424A2 (fr) |
| NO (1) | NO20052859L (fr) |
| WO (1) | WO2004043923A1 (fr) |
| ZA (1) | ZA200503698B (fr) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA200603113B (en) * | 2003-09-26 | 2007-08-29 | Jubilant Organosys Ltd | Process for the preparation of risperidone |
| WO2009077551A1 (fr) * | 2007-12-18 | 2009-06-25 | Janssen Pharmaceutica Nv | Procédé de préparation de la rispéridone |
| US8772345B2 (en) | 2011-08-03 | 2014-07-08 | Southwest Research Institute | Oximes for treatment of peripheral and central nervous system exposure to acetyl cholinesterase inhibitors |
| US8653108B1 (en) | 2011-08-03 | 2014-02-18 | Southwest Research Institute | Oximes for treatment of peripheral and central nervous system exposure to acetyl cholinesterase inhibitors |
| US9162983B2 (en) | 2013-05-22 | 2015-10-20 | Southwest Research Institute | Reactivators of organophosphorous inhibited acetylcholinesterase |
| CN104557918A (zh) * | 2014-12-12 | 2015-04-29 | 瑞阳制药有限公司 | 苯并异恶唑类抗精神病药利培酮的制备方法 |
| CN107422055A (zh) * | 2017-07-27 | 2017-12-01 | 天津药物研究院药业有限责任公司 | 一种利培酮原料或制剂中杂质的检测方法 |
| CN108445101B (zh) * | 2018-03-16 | 2021-01-01 | 安徽新世纪药业有限公司 | 一种利培酮口服溶液有关物质的检测方法 |
| CN109438443A (zh) * | 2018-12-24 | 2019-03-08 | 浙江工业大学上虞研究院有限公司 | 利培酮的制备方法 |
| CN111777601B (zh) * | 2020-05-23 | 2021-07-16 | 白银京宇新药业有限公司 | 一种6-氟-3-(4-哌啶基)-1，2苯并异噁唑盐酸盐的制备方法 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3946022A (en) * | 1974-03-04 | 1976-03-23 | Richardson-Merrell Inc. | Piperidine derivatives |
| US4335127A (en) | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
| US4342870A (en) | 1980-03-28 | 1982-08-03 | Janssen Pharmaceutica N.V. | Novel 3-(1-piperidinylalkyl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives |
| US4408054A (en) * | 1981-11-12 | 1983-10-04 | Hoechst-Roussel Pharmaceuticals Inc. | Oximes of 4-benzoyl-piperidines |
| US4804663A (en) | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
| CA2000786C (fr) | 1988-11-07 | 1999-01-26 | Cornelus G. M. Janssen | 3-piperidinyl-1,2-benzisoxazoles |
| GB9008850D0 (en) * | 1990-04-19 | 1990-06-13 | Janssen Pharmaceutica Nv | Novel 2,9-disubstituted-4h-pyridol(1,2-a)pyrimidin-4-ones |
| ES2050069B1 (es) * | 1992-07-10 | 1994-12-16 | Vita Invest Sa | Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino)etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido(1,2-a) pirimidin-4-ona. |
| ES2074966B1 (es) | 1994-02-11 | 1996-06-16 | Vita Invest Sa | Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-benzo(d)isoxazol-3-il)piperidin-1-il)-etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido-(1,2-a)pirimidin-4-ona. |
| CZ295402B6 (cs) | 2000-05-05 | 2005-08-17 | Rpg Life Sciences Limited | Způsob přípravy antipsychotického 3-[2-[4-(6-fluor-1,2-benzizoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-onu |
| US20020115672A1 (en) | 2000-08-08 | 2002-08-22 | Barnaba Krochmal | Preparation of risperidone |
| EP1982980A1 (fr) | 2000-08-14 | 2008-10-22 | Teva Pharmaceutical Industries Ltd. | Forme cristalline de la rispéridone |
| HU227118B1 (en) | 2001-11-13 | 2010-07-28 | Egis Gyogyszergyar Nyilvanosan | Process for the preparation of 3-{2-[4-(6-fluoro-1,2-benzizoxazol-3-yl)-1-piperidinyl]-ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one |
| MXPA06007654A (es) * | 2003-12-31 | 2006-09-04 | Warner Lambert Co | Derivados de piperidina n-sustituidos. |
-
2003
- 2003-11-07 EP EP03779870A patent/EP1560814A1/fr not_active Withdrawn
- 2003-11-07 AU AU2003288017A patent/AU2003288017A1/en not_active Abandoned
- 2003-11-07 CN CNB2003801049621A patent/CN100390146C/zh not_active Expired - Fee Related
- 2003-11-07 WO PCT/EP2003/012504 patent/WO2004043923A1/fr not_active Application Discontinuation
- 2003-11-13 AR ARP030104179A patent/AR041954A1/es unknown
- 2003-11-13 US US10/705,926 patent/US7405298B2/en not_active Expired - Fee Related
-
2005
- 2005-05-09 ZA ZA200503698A patent/ZA200503698B/en unknown
- 2005-05-12 HR HR20050424A patent/HRP20050424A2/xx not_active Application Discontinuation
- 2005-06-13 NO NO20052859A patent/NO20052859L/no not_active Application Discontinuation
-
2008
- 2008-06-18 US US12/141,596 patent/US20080262227A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| HRP20050424A2 (en) | 2006-08-31 |
| NO20052859L (no) | 2005-08-05 |
| CN100390146C (zh) | 2008-05-28 |
| WO2004043923A1 (fr) | 2004-05-27 |
| US7405298B2 (en) | 2008-07-29 |
| AR041954A1 (es) | 2005-06-01 |
| AU2003288017A1 (en) | 2004-06-03 |
| NO20052859D0 (no) | 2005-06-13 |
| EP1560814A1 (fr) | 2005-08-10 |
| US20080262227A1 (en) | 2008-10-23 |
| CN1720228A (zh) | 2006-01-11 |
| US20040097523A1 (en) | 2004-05-20 |
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